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Byline: K. Chuah, M. Abdul Aziz, J. Jayamani Accuracy of ionization chamber (IC) to measure the scatter output factor (S[sub]cp) of a linear accelerator (linac) is crucial, especially in small [...]

Nanotechnology has advanced significantly; however, little is known about the potential implications on human health-related issues, particularly blood carrying enzymes. Ionic liquids are also well-recognized for maintaining the structure and activity of enzymes. In this regard, we delineate a facile synthetic approach of preparation of Fe 3 O 4 nanoparticles (NPs) as well as choline hydroxide [CH][OH] ionic liquid (IL)-supported Fe 3 O 4 NPs (Fe 3 O 4 -CHOH). This approach of combining magnetic nanoparticles (MNPs) with IL results in distinctive properties, which may offer enormous utility in the field of biomedical research due to the effortless separation of MNPs by an external magnetic field. Detailed characterization of MNPs including Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) was carried out. The biomolecular interactions of Fe 3 O 4 and Fe 3 O 4 -CHOH NPs with cytochrome c (Cyt c) were studied in detail using various spectroscopic and microscopic techniques. From spectroscopic studies, it can be concluded that the secondary structure of Cyt c is more stable in the presence of Fe 3 O 4 -CHOH NPs than Fe 3 O 4 NPs. The binding constant of Cyt c in the presence of MNPs was also calculated using the Benesi-Hildebrand equation. Furthermore, dynamic light scattering (DLS), ζ-potential, and microscopic studies were performed to study the interaction of Cyt c with MNPs. These studies provided evidence favoring the formation of bionanoconjugates of Cyt c with MNPs. Moreover, the enzymatic activity of Cyt c increases in the presence of both MNPs. The peroxidase activity of Cyt c in MNPs explicitly elucidates that the enzyme is preserved for a long time in the presence of Fe 3 O 4 -CHOH NPs. Later on, TEM and field emission scanning electron microscopy (FESEM) were also performed to gather more information regarding the morphology of Cyt c in the presence of MNPs.

Purpose: This study aims to determine the percentage depth dose (PDD) of a phantom material made from soy-lignin bonded Rhizophora spp. particleboard coated with a gloss finish by using Monte Carlo Geant4 Application for Tomographic Emission (GATE) simulation., Materials and Methods: The particleboard was fabricated using a hot pressing technique at target density of 1.0 g·cm -3 and the elemental fraction was recorded for the simulation. The PDD was simulated in the GATE simulation using the linear accelerator Elekta Synergy model for the water phantom and Rhizophora phantom, and the results were compared with the experimental PDD performed by several studies. Beam flatness and beam symmetry were also measured in this study., Results: The simulated PDD for Rhizophora and water was in agreement with the experimental PDD of water with overall discrepancies of 0% to 8.7% at depth ranging from 1.0 to 15.0 cm. In the GATE simulation, all the points passed the clinical 3%/3 mm criterion in comparison with water, with the final percentage of 2.34% for Rhizophora phantom and 2.49% for the water phantom simulated in GATE. Both the symmetries are all within the range of an acceptable value of 2.0% according to the recommendation, with the beam symmetry of the water phantom and Rhizophora phantom at 0.58% and 0.28%, respectively., Conclusions: The findings of this study provide the necessary foundation to confidently use the phantom for radiotherapy purposes, especially in treatment planning., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Medical Physics.)

Risk management constitutes an essential component of the Quality Management System (QMS) of medical laboratories. The international medical laboratory standard for quality and competence, International Standards Organization (ISO) 15189, in its 2012 version, specified risk management for the first time. Since then, there has been much focus on this subject. We authors aimed to develop a practical tool for risk management in a clinical laboratory that contains five major cyclical steps: risk identification, quantification, prioritization, mitigation, and surveillance. The method for risk identification was based on a questionnaire that was formulated by evaluating five major components of laboratory processes, namely i) Specimen, ii) Test system, iii) Reagent, iv) Environment, and v) Testing. All risks that would be identified using the questionnaire can be quantified by calculating the risk priority number (RPN) using the tool, failure modes, and effects analysis (FMEA). Based on the calculated RPN, identified risks then shall be prioritized and mitigated. Based on our collective laboratory management experience, we authors also enlisted and scheduled a few process-specific quality assurances (QA) activities. The listed QA activities intend to monitor new risk emergence and re-emergence of those previously mitigated ones. We authors believe that templates of risk identification, risk quantification, and risk surveillance presented in this article will serve as ready references for supervisors of clinical laboratories., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Jayamani et al.)

Blackgram, an important pulse crop of India and other Asian countries, is a rich source of protein. Genetic improvement in this crop is generally slow-paced due to the lack of wide genetic variability available for selection. To create variability for important morphological traits and yield, induced mutagenesis was attempted in a popular blackgram cultivar CO 6 using gamma rays (γ rays- 60 Co) and a combination of ethyl methanesulphonate (EMS) and gamma rays. In M 1 generation, the mutagenic treatments of 200 Gy γ rays and 200 Gy + 20 mM EMS showed a high percentage of viable and chlorophyll mutants. However, in M 2 generation, 400 Gy + 20 mM EMS generated a higher proportion of viable mutations. A broad spectrum of viable macro mutants namely variation in growth habit, duration, size of leaf and pod, nature of pod and seed, seed yield and protruded stigma mutant were observed. The combination treatments exhibited a maximum frequency of viable macro mutations. Among viable macro mutations, the growth habit mutants recorded maximum frequency, followed by leaf mutants and pod mutants. The protruded stigma mutant was isolated at the higher dose of 400 Gy of γ rays. Studies on palynological traits among fertile and sterile plants using Scanning Electron Microscopy (SEM) revealed variations in pollen and anther length and shape among the mutants. The pollen lumina and muri shape in the fertile plant were observed as polygonal and narrow straight, whereas it was collapsed in the sterile plant. The inheritance pattern for most of the viable macro mutants was true-breeding which was further confirmed in the M 3 generation. These viable mutants could be used for the blackgram improvement program., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The question of what determines whether cells are big or small has been the focus of many studies because it is thought that such determinants underpin the coupling of cell growth with cell division. In contrast, what determines the overall pattern of how cell size is distributed within a population of wild type or mutant cells has received little attention. Knowing how cell size varies around a characteristic pattern could shed light on the processes that generate such a pattern and provide a criterion to identify its genetic basis. Here, we show that cell size values of wild type Saccharomyces cerevisiae cells fit a gamma distribution, in haploid and diploid cells, and under different growth conditions. To identify genes that influence this pattern, we analyzed the cell size distributions of all single-gene deletion strains in Saccharomyces cerevisiae We found that yeast strains which deviate the most from the gamma distribution are enriched for those lacking gene products functioning in gene expression, especially those in transcription or transcription-linked processes. We also show that cell size is increased in mutants carrying altered activity substitutions in Rpo21p/Rpb1, the largest subunit of RNA polymerase II (Pol II). Lastly, the size distribution of cells carrying extreme altered activity Pol II substitutions deviated from the expected gamma distribution. Our results are consistent with the idea that genetic defects in widely acting transcription factors or Pol II itself compromise both cell size homeostasis and how the size of individual cells is distributed in a population., (Copyright © 2019 by the Genetics Society of America.)

Competing Interests: None

Heat shock factor 1 is the master transcriptional regulator of molecular chaperones and binds to the same cis-acting heat shock element (HSE) across the eukaryotic lineage. In budding yeast, Hsf1 drives the transcription of ∼20 genes essential to maintain proteostasis under basal conditions, yet its specific targets and extent of inducible binding during heat shock remain unclear. Here we combine Hsf1 chromatin immunoprecipitation sequencing (seq), nascent RNA-seq, and Hsf1 nuclear depletion to quantify Hsf1 binding and transcription across the yeast genome. We find that Hsf1 binds 74 loci during acute heat shock, and these are linked to 46 genes with strong Hsf1-dependent expression. Notably, Hsf1's induced DNA binding leads to a disproportionate (∼7.5-fold) increase in nascent transcription. Promoters with high basal Hsf1 occupancy have nucleosome-depleted regions due to the presence of "pioneer factors." These accessible sites are likely critical for Hsf1 occupancy as the activator is incapable of binding HSEs within a stably positioned, reconstituted nucleosome. In response to heat shock, however, Hsf1 accesses nucleosomal sites and promotes chromatin disassembly in concert with the Remodels Structure of Chromatin (RSC) complex. Our data suggest that the interplay between nucleosome positioning, HSE strength, and active Hsf1 levels allows cells to precisely tune expression of the proteostasis network.

Excess accumulation of collagen (fibrosis) is the hallmark of many fibrotic diseases such as keloids, hypertrophic scars, etc. The inhibition of collagen fibrillation during its accumulation is a therapeutic way to limit the fibrosis. Herein, the effect of Ferulic acid (FA), a natural phenolic acid compound, on collagen fibrillation is studied using biophysical methods. Optical density (OD) and microscopic analysis indicate that FA inhibits collagen self-association, and the inhibitory efficiency depends on the concentration and temperature. The absence of an increase in OD for matured collagen fibrillar solution upon addition of FA followed by collagen solution indicates that FA could also terminates the progression of preformed collagen fibrils. Spectroscopic measurements indicate that collagen retains its unique triple helical structure in the presence of FA. Saturation Transfer Difference NMR suggests that FAs are in proximity to collagen while fluorescence quenching upon addition of FA proposes that FA most likely binds to the telopeptide regions of collagen. Enzymatic studies suggest that FA protects collagen from enzymatic degradation. The current study demonstrates that FA is a potential inhibitor of collagen fibrillation and its propagation and thus it can be considered for therapeutic studies to make FA as a remedy for the plaques related to collagen deposition., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Study Design: A retrospective study of the ventral displacement of dorsal spinal cord (VDDSC) spectrum pathophysiology and grading., Purpose: This study aimed at examining the pathophysiology of VDDSC between D3 and D7, using magnetic resonance imaging (MRI) correlation and severity grading., Overview of Literature: The pathologies that lead to VDDSC were previously discussed in various articles. We attempted to group these pathological conditions under a single spectrum, and grade them according to their severity., Methods: We reviewed the MRI images of the dorsal spines of 1,350 patients over a period of 4 years (February 2013-February 2017); all MRI images were analyzed by two experienced radiologists., Results: Of the 1,350 patients, 28 exhibited VDDSC between D3 and D7. Additional findings included ventral transdural herniation of the spinal cord (n=10), anterior spinal cord adhesion (n=7), arachnoid web (n=6), and arachnoid cyst (n=5)., Conclusions: We grouped the pathologies that lead to VDDSC at the thoracic level into a single spectrum of varying severity and graded VDDSC, from mild to severe.

Models for regulation of the eukaryotic heat shock response typically invoke a negative feedback loop consisting of the transcriptional activator Hsf1 and a molecular chaperone. Previously we identified Hsp70 as the chaperone responsible for Hsf1 repression and constructed a mathematical model that recapitulated the yeast heat shock response (Zheng et al., 2016). The model was based on two assumptions: dissociation of Hsp70 activates Hsf1, and transcriptional induction of Hsp70 deactivates Hsf1. Here we validate these assumptions. First, we severed the feedback loop by uncoupling Hsp70 expression from Hsf1 regulation. As predicted by the model, Hsf1 was unable to efficiently deactivate in the absence of Hsp70 transcriptional induction. Next, we mapped a discrete Hsp70 binding site on Hsf1 to a C-terminal segment known as conserved element 2 (CE2). In vitro, CE2 binds to Hsp70 with low affinity (9 µM), in agreement with model requirements. In cells, removal of CE2 resulted in increased basal Hsf1 activity and delayed deactivation during heat shock, while tandem repeats of CE2 sped up Hsf1 deactivation. Finally, we uncovered a role for the N-terminal domain of Hsf1 in negatively regulating DNA binding. These results reveal the quantitative control mechanisms underlying the heat shock response., Competing Interests: JK, XZ, NP, ZF, JA, KV, DG, AK, DP No competing interests declared, (© 2018, Krakowiak et al.)

Excess accumulation of collagen (fibrosis) undergoes self-aggregation, which leads to fibrillar collagen, on the extracellular matrix is the hallmark of a number of diseases such as keloids, hypertrophic scars, and systemic scleroderma. Direct inhibition or disintegration of collagen fibrils by small molecules offer a therapeutic approach to prevent or treat the diseases related to fibrosis. Herein, the anti-fibrotic property of Glucono-δ-lactone (GdL), known as acidifier, on the fibrillation and its disintegration of collagen was investigated. As collagen fibrillation is pH dependent, the pH modulation property of GdL is attractive to inhibit self-association of collagen. Optical density and microscopic data indicate that GdL elicits concentration-dependent fibril inhibition and also disintegrates pre-formed collagen fibrils. The simultaneous pH analysis showed that the modulation(lowering) of pH by GdL is the primary cause for its anti-fibrotic activity. The intact triple helical structure of collagen upon treatment of GdL suggests that collagen fibril disintegration can be achieved without affecting the native structure of collagen which is essential for any anti-fibrotic agents. Saturation transfer difference (STD) NMR result reveals that GdL is in proximity to collagen. The present results thus suggest that GdL provides a lead to design novel anti-fibrotic agents for the pathologies related to collagen deposition., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Number of incurable diseases associated with neurodegenerative syndromes like Alzheimer's, and Parkinson's, are owing to protein aggregation which leads to amyloid fibril formation. In vitro, such fibrillation depends on concentration, temperature, pH, ionic strength, organic solvents, agitation, and stirring, which play a crucial role in understanding the mechanism of fibrillation as well as to identify potential inhibitors for fibrillation. Although these parameters were considered, the precise repeatability of amyloid fibrillation kinetics between laboratories remains challenging. Herein, we have demonstrated that another important parameter such as diameter of the vial in which protein undergoes fibrillation play a key role in the amyloid fibrillation. The various biophysical analyses indicated that the lag time, elongation, and the amount of fibril formation was significantly reduced with decreasing the diameter of the reaction vial from 24 to 15mm. Further, the minimum amount of protein required for fibrillation was determined by the diameter of the vial. The observed fibrillation difference in different vials is most likely due to the variation in the interface area between hydrophobic (air) and hydrophilic (water) surfaces as the diameter of the vial changes. The current results have a major role in the design of drug screening assays for amyloid inhibition., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mediator is an evolutionarily conserved coactivator complex essential for RNA polymerase II transcription. Although it has been generally assumed that in Saccharomyces cerevisiae, Mediator is a stable trimodular complex, its structural state in vivo remains unclear. Using the "anchor away" (AA) technique to conditionally deplete select subunits within Mediator and its reversibly associated Cdk8 kinase module (CKM), we provide evidence that Mediator's tail module is highly dynamic and that a subcomplex consisting of Med2, Med3, and Med15 can be independently recruited to the regulatory regions of heat shock factor 1 (Hsf1)-activated genes. Fluorescence microscopy of a scaffold subunit (Med14)-anchored strain confirmed parallel cytoplasmic sequestration of core subunits located outside the tail triad. In addition, and contrary to current models, we provide evidence that Hsf1 can recruit the CKM independently of core Mediator and that core Mediator has a role in regulating postinitiation events. Collectively, our results suggest that yeast Mediator is not monolithic but potentially has a dynamic complexity heretofore unappreciated. Multiple species, including CKM-Mediator, the 21-subunit core complex, the Med2-Med3-Med15 tail triad, and the four-subunit CKM, can be independently recruited by activated Hsf1 to its target genes in AA strains., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

In fission yeast, the ste11 gene encodes the master regulator initiating the switch from vegetative growth to gametogenesis. In a previous paper, we showed that the methylation of H3K4 and consequent promoter nucleosome deacetylation repress ste11 induction and cell differentiation (Materne et al., 2015) but the regulatory steps remain poorly understood. Here we report a genetic screen that highlighted H2B deubiquitylation and the RSC remodeling complex as activators of ste11 expression. Mechanistic analyses revealed more complex, opposite roles of H2Bubi at the promoter where it represses expression, and over the transcribed region where it sustains it. By promoting H3K4 methylation at the promoter, H2Bubi initiates the deacetylation process, which decreases chromatin remodeling by RSC. Upon induction, this process is reversed and efficient NDR (nucleosome depleted region) formation leads to high expression. Therefore, H2Bubi represses gametogenesis by opposing the recruitment of RSC at the promoter of the master regulator ste11 gene.

Chromatin is a complex of proteins, RNA and DNA that constitutes the physiological state of the genome. Its basic structure is essentially the same in nearly all eukaryotes, from single-celled yeasts to the most complex multicellular organisms (exceptions include the chromatin of dinoflagellates and vertebrate sperm). Its fundamental role is to package the genome in a sufficiently compact form that allows comparatively very large molecules of DNA to fit inside the cell's nucleus. In human cells, the contour length of the DNA molecules comprising the largest chromosomes is nearly 10,000 times the diameter of the nucleus (typically on the order of 5-10 microns). How is this compaction accomplished? Through multiple layers of folding., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The phosphorylation of the RNA polymerase II C-terminal domain (CTD) plays a key role in delineating transcribed regions within chromatin by recruiting histone methylases and deacetylases. Using genome-wide nucleosome mapping, we show that CTD S2 phosphorylation controls nucleosome dynamics in the promoter of a subset of 324 genes, including the regulators of cell differentiation ste11 and metabolic adaptation inv1. Mechanistic studies on these genes indicate that during gene activation a local increase of phospho-S2 CTD nearby the promoter impairs the phospho-S5 CTD-dependent recruitment of Set1 and the subsequent recruitment of specific HDACs, which leads to nucleosome depletion and efficient transcription. The early increase of phospho-S2 results from the phosphorylation of the CTD S2 kinase Lsk1 by MAP kinase in response to cellular signalling. The artificial tethering of the Lsk1 kinase at the ste11 promoter is sufficient to activate transcription. Therefore, signalling through the CTD code regulates promoter nucleosomes dynamics.

Proteins under stressful conditions can lead to the formation of an ordered self-assembled structure, referred to as amyloid fibrils, to which many neurodegenerative diseases such as Type II diabetes, Alzheimer's, Parkinson's, Huntington's, etc., are attributed. Inhibition of amyloid fibril formation using natural products is one of the main therapeutic strategies to prevent the progression of these diseases. Polyphenols are the mostly consumed as antioxidants in a human nutrition. Herein, we have studied the effect of a simple polyphenol, gallic acid (GA), one of the main components in plant tissues, especially in tea leaves, on the insulin amyloid fibril formation. Different biophysical characterizations such as turbidity, atomic force microscopy (AFM), Thioflavin T (ThT) assays, circular dichroism, and Fourier transform-infrared spectroscopy have been used to analyze the inhibition of amyloid fibril formation. The occurrence of fibrils in an AFM image and ThT fluorescence enhancement confirms the formation of insulin amyloid fibrils when incubated under acidic pH 2 at 65 °C. In the presence of GA, absence of fibrils in AFM image and no change in the intensity of ThT fluorescence confirms the inhibition of insulin amyloid fibrils by GA. Spectroscopic results reveal that GA inhibits the conformational transition of α-helix → β-sheet, which is generally induced during the insulin fibril formation. It was found that the inhibitory effect of GA is concentration dependent and non-linear. Based on the observed results, we propose that GA interacts with native insulin, preventing nuclei formation, which is essential for fibril growth, thereby inhibiting the amyloid fibril formation. The present results thus demonstrate that GA can effectively inhibit insulin amyloid fibril formation in vitro., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Recent seminal studies have established neurodegeneration, cognitive waning and/or β-amyloid deposition due to chronic copper intoxication via drinking water in healthy animals; henceforth, fuelling the debate all again over the safe levels of copper in the drinking water. This review encompasses the contemporary imperative animal studies in which the effect of chronic copper toxicity (especially via drinking water) was evaluated on the central nervous system and memory of uncompromised animals along with discussing the future perspectives., (Copyright © 2014 Elsevier Inc. All rights reserved.)

It is widely accepted that transcriptional regulation of eukaryotic genes is intimately coupled to covalent modifications of the underlying chromatin template, and in certain cases the functional consequences of these modifications have been characterized. Here we present evidence that gene activation in the silent heterochromatin of the yeast Saccharomyces cerevisiae can occur in the context of little, if any, covalent histone modification. Using a SIR-regulated heat shock-inducible transgene, hsp82-2001, and a natural drug-inducible subtelomeric gene, YFR057w, as models we demonstrate that substantial transcriptional induction (>200-fold) can occur in the context of restricted histone loss and negligible levels of H3K4 trimethylation, H3K36 trimethylation and H3K79 dimethylation, modifications commonly linked to transcription initiation and elongation. Heterochromatic gene activation can also occur with minimal H3 and H4 lysine acetylation and without replacement of H2A with the transcription-linked variant H2A.Z. Importantly, absence of histone modification does not stem from reduced transcriptional output, since hsp82-ΔTATA, a euchromatic promoter mutant lacking a TATA box and with threefold lower induced transcription than heterochromatic hsp82-2001, is strongly hyperacetylated in response to heat shock. Consistent with negligible H3K79 dimethylation, dot1Δ cells lacking H3K79 methylase activity show unimpeded occupancy of RNA polymerase II within activated heterochromatic promoter and coding regions. Our results indicate that large increases in transcription can be observed in the virtual absence of histone modifications often thought necessary for gene activation.

Sexual reproduction is a fundamental aspect of eukaryotic cells, and a conserved feature of gametogenesis is its dependency on a master regulator. The ste11 gene was isolated more than 20 years ago by the Yamamoto laboratory as a suppressor of the uncontrolled meiosis driven by a pat1 mutant. Numerous studies from this laboratory and others have established the role of the Ste11 transcription factor as the master regulator of the switch between proliferation and differentiation in fission yeast. The transcriptional and post-transcriptional controls of ste11 expression are intricate, but most are not redundant. Whereas the transcriptional controls ensure that the gene is transcribed at a high level only when nutrients are rare, the post-transcriptional controls restrict the ability of Ste11 to function as a transcription factor to the G1-phase of the cell cycle from where the differentiation programme is initiated. Several feedback loops ensure that the cell fate decision is irreversible. The complete panel of molecular mechanisms operating to warrant the timely expression of the ste11 gene and its encoded protein basically mirrors the advances in the understanding of the numerous ways by which gene expression can be modulated.

Hyperphosphorylated and aggregated human protein tau constitutes a hallmark of a multitude of neurodegenerative diseases called tauopathies, exemplified by Alzheimer's disease. In spite of an enormous amount of research performed on tau biology, several crucial questions concerning the mechanisms of tau toxicity remain unanswered. In this paper we will highlight some of the processes involved in tau biology and pathology, focusing on tau phosphorylation and the interplay with oxidative stress. In addition, we will introduce the development of a human tau-expressing yeast model, and discuss some crucial results obtained in this model, highlighting its potential in the elucidation of cellular processes leading to tau toxicity.

Unraveling the biochemical and genetic alterations that control the aggregation of protein tau is crucial to understand the etiology of tau-related neurodegenerative disorders. We expressed wild type and six clinical frontotemporal dementia with parkinsonism (FTDP) mutants of human protein tau in wild-type yeast cells and cells lacking Mds1 or Pho85, the respective orthologues of the tau kinases GSK3β and cdk5. We compared tau phosphorylation with the levels of sarkosyl-insoluble tau (SinT), as a measure for tau aggregation. The deficiency of Pho85 enhanced significantly the phosphorylation of serine-409 (S409) in all tau mutants, which coincided with marked increases in SinT levels. FTDP mutants tau-P301L and tau-R406W were least phosphorylated at S409 and produced the lowest levels of SinT, indicating that S409 phosphorylation is a direct determinant for tau aggregation. This finding was substantiated by the synthetic tau-S409A mutant that failed to produce significant amounts of SinT, while its pseudophosphorylated counterpart tau-S409E yielded SinT levels higher than or comparable to wild-type tau. Furthermore, S409 phosphorylation reduced the binding of protein tau to preformed microtubules. The highest SinT levels were found in yeast cells subjected to oxidative stress and with mitochondrial dysfunction. Under these conditions, the aggregation of tau was enhanced although the protein is less phosphorylated, suggesting that additional mechanisms are involved. Our results validate yeast as a prime model to identify the genetic and biochemical factors that contribute to the pathophysiology of human tau., (© 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)